6PGR
Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-BROMO-N-(1H-INDOL-4-YL)-1-BENZOTHIOPHENE-2-CARBOXAMIDE
Summary for 6PGR
| Entry DOI | 10.2210/pdb6pgr/pdb |
| Related | 5V15 5V4J |
| Descriptor | Deoxyhypusine synthase, 6-bromo-N-(1H-indol-4-yl)-1-benzothiophene-2-carboxamide (3 entities in total) |
| Functional Keywords | deoxyhypusine, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 83169.73 |
| Authors | Klein, M.G.,Ambrus-Aikelin, G. (deposition date: 2019-06-24, release date: 2020-04-01, Last modification date: 2023-10-11) |
| Primary citation | Tanaka, Y.,Kurasawa, O.,Yokota, A.,Klein, M.G.,Ono, K.,Saito, B.,Matsumoto, S.,Okaniwa, M.,Ambrus-Aikelin, G.,Morishita, D.,Kitazawa, S.,Uchiyama, N.,Ogawa, K.,Kimura, H.,Imamura, S. Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase. J.Med.Chem., 63:3215-3226, 2020 Cited by PubMed Abstract: Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound () led to bromobenzothiophene () with potent inhibitory activity against DHPS. X-ray crystallographic analysis of complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors. PubMed: 32142284DOI: 10.1021/acs.jmedchem.9b01979 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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